Investigating the molecular basis of how epigenomic and genomic factors influence susceptibility to Nonalcoholic fatty liver disease (NAFLD) in humans using human NAFLD samples is desirable but frequently impractical. In contrast, using relevant animal models that resemble human NAFLD development may substantially overcome the many limitations of human-only studies and provide important clues regarding the molecular consequences of etiological factors linked to NAFLD susceptibility and severity. This Inter-Agency Agreement (IAA) will investigate the extent of molecular changes indicative of NAFLD-associated liver injury to assist in identifying susceptible individuals. Thus, we hypothesize that (a) the status of individual epigenomic hepatic phenotypes is a fundamental factor that predetermines susceptibility to NAFLD; and (b) an evaluation of epigenomic hepatic phenotypes in a genetically heterogeneous mouse population will assist in identifying individuals susceptible to NAFLD. To test the hypothesis, we are using Collaborative Cross mice, a state-of-the-art mouse population model, to investigate the induction of NAFLD by a Western Diet. Next generation sequencing, chromatin immunoprecipitation with DNA microarray methodology (Chip-on-chip) and quantitative RT-PCR will be used to assess whole genome-scale epigenomic changes and expression of protein-coding and non-coding RNAs, especially microRNAs, in plasma, white blood cells, and livers.